The Nargenicins are a new class of structurally novel antibiotics which exhibit significant activity against drug-resistant microbial strains. The total synthesis of nodusmicin, a representative member of this class, is the principal objective of this investigation. In order to confront the unique structural and stereochemical challenge of nodusmicin and its congeners we intend to develop new methodology, specifically: 1) a procedure for generation of functionalized medium-ring lactones, and 2) a stereorational method for development of acyclic compounds containing remote, oxygenated chiral centers. Each of these new methods is potentially applicable to the synthesis of other biologically interesting compounds, and the scope and limitations of the procedures will be examined in model studies. The proposed stereocontrolled, linear synthesis of nodusmicin represents a major divergence from the previous strategies which have been employed to synthesize compounds containing elements of remote acyclic chirality. In addition, the proposed synthetic route to nodusmicin is intended to be applicable to the preparation of related nargenicin antibiotics as well as new analogs. A degradation of nodusmicin and Nargenicin A(1) is planned; this study will provide authentic samples of intermediates along the proposed synthetic path. Compounds derived from the model and degradation studies will be submitted for biological testing, as will intermediates from the total synthesis of nodusmicin.